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• Response to M Guido and M Rugge
  Stephen D Ryder
  Published on: 18 April 2016
• Liver fibrosis: natural history may be affected by the biopsy sample
  Maria Guido
  Published on: 18 April 2016

• Published on: 18 April 2016

  Response to M Guido and M Rugge

  • Stephen D Ryder, Consultant Hepatologist

  Dear Editor

  Mario Guido and Massimo Rugge make important points about the interpretation of liver biopsy if the sample is small.[1]

  Our study [2] was accepted for publication before the Colloredo article was published in the Journal of Hepatology and we would agree that the standards for accepting a liver biopsy as adequate have changed in the light of their data.

  With respect to our study,...

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  Dear Editor

  Mario Guido and Massimo Rugge make important points about the interpretation of liver biopsy if the sample is small.[1]

  Our study [2] was accepted for publication before the Colloredo article was published in the Journal of Hepatology and we would agree that the standards for accepting a liver biopsy as adequate have changed in the light of their data.

  With respect to our study, we can confirm that the median number of portal tracts per biopsy was 15 in the second biopsy where that showed regression with only no biopsy having less than 11. Analysis of size and portal tract number in the groups of patients who progressed, remained stable or regressed showed no difference. In particular the second biopsy sample in "regressors" contained a higher median number of portal tracts than the index biopsy. Using the critera established by Brunetti et al, only six biopsies from the whole cohort would have been characterised by them as inadequate and omitting these patients from the analysis does not alter the results.

  We therefore feel that the biopsy size in our study is adequate and the conclusions remain valid.

  References

  (1) Guido M and Rugge M. Liver fibrosis: natural history may be affected by the biopsy sample [electronic response to Ryder; Progression of hepatic fibrosis in patients with hepatitis C: a prospective repeat liver biopsy study] gutjnl.com 2004http://gut.bmjjournals.com/cgi/eletters/53/3/451#398

  (2) S D Ryder. Progression of hepatic fibrosis in patients with hepatitis C: a prospective repeat liver biopsy study. Gut 2004; 53: 451-455

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  Conflict of Interest:
  None declared.

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• Published on: 18 April 2016

  Liver fibrosis: natural history may be affected by the biopsy sample

  • Maria Guido
  • Other Contributors:
    • Massimo Rugge

  Dear Editor

  We read with great interest the article by Ryder and the Trent hepatitis C Study Group,[1] addressing the issue of fibrosis progression in untreated patients with chronic hepatitis C. After examining a large series of paired liver biopsies (median inter-biopsy interval: 2.5 years), the Authors conclude that, even in patients with a "histologically mild" presentation, chronic hepatitis C is characterized...

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  Dear Editor

  We read with great interest the article by Ryder and the Trent hepatitis C Study Group,[1] addressing the issue of fibrosis progression in untreated patients with chronic hepatitis C. After examining a large series of paired liver biopsies (median inter-biopsy interval: 2.5 years), the Authors conclude that, even in patients with a "histologically mild" presentation, chronic hepatitis C is characterized by progressive fibrosis. The histological assessment of liver fibrosis in chronic liver diseases is a fields of our interest and our experience prompts us to raise a methodological issue concerning Ryder's study.

  While many attempts have been made to standardize non-invasive tests for predicting liver fibrosis, biopsy sampling is currently considered the standard reference for grading and staging chronic hepatitis. Biopsy sampling error and sample size have proved the major sources of bias in liver fibrosis assessment and both variables should be taken into account when the outcome of histology guides patient management decisions.

  Two studies [2,3] have recently demonstrated that the traditional concept of “adequate liver biopsy sample” (core biopsy 1.5 cm long and/or containing 4/5 portal tracts) is no longer acceptable. Both studies consistently demonstrated that the stage of disease is under-rated in biopsy samples shorter than 2-2.5 cm and/or thinner than 1.4-1.2 mm. More recently, a well-designed study by Brunetti et al.[4] showed that fine needle biopsies also underestimate the stage of chronic hepatitis C as revealed by large needle biopsies. The critical factor in staging fibrosis is the number of complete portal tracts included in the sample, the range of 11-15 complete portal tracts being the minimum requirement for a reliable histological assessment.[2] In practice, this means that, when paired biopsies are used to assess fibrosis progression, the biopsy size and/or number of complete portal tracts has to be comparable in the two samples considered: any progression or regression of fibrosis may be biased, due to the inconsistent size of the paired liver biopsy samples (i.e. initial small versus larger follow-up biopsy, or large initial versus smaller follow-up biopsy).

  In the Ryder study, the threshold for adequacy was the presence of more than 5 portal tracts and the Authors did not say whether the paired biopsies were comparable in terms of the number of portal triads. Fibrosis regression (10%) was interpreted as "presumably" being due to "a combination of observer error and sampling variation". We agree that this is a possible interpretation of "regressive" fibrosis, but we would suggest that a similar interpretation should be also considered for "progressing" fibrosis.

  Our concern is of some practical importance, since the Ryder's study demonstrates that fibrosis progresses in less than 3 years in 33% of untreated hepatitis C patients (including those with persistently normal ALT). This means that the strategy that excludes subjects with mild disease from treatment (as recommended by current guidelines) needs to be reconsidered.

  The size of liver biopsy samples is feasibly one of the clinical variable pertaining to in vivo studies and it would be unreasonable to disregard liver biopsies that fail to fulfil current adequacy criteria entirely. Nonetheless, the considerable bias that "inadequate" biopsy material can introduce makes it necessary to pay more attention to ensure an exhaustive description of the analyzed samples (too often neglected in the "Methods section" of otherwise valuable articles). This methodological recommendation applies both to pathologists involved in clinical trials and to manuscript reviewers.[5]

  References

  1. Ryder SD. Progression of liver fibrosis in patient with hepatitis C: a prospective repeat liver biopsy study. Gut 2004; 53:451-5

  2. Colloredo G, Guido M, Sonzogni A, et al. Impact of liver biopsy size on histological evaluation of chronic viral hepatitis: the smaller the sample, the milder the disease. J Hepatol 2003; 39:239-44.

  3. Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C.Hepatology. 2003; 38:1449-57.

  4. Brunetti E, Silini E, Pistorio A et al. Coarse vs. fine needle aspiration biopsy for the assessment of diffuse liver disease from hepatitis C virus-related chronic hepatitis. J Hepatol 2004; 40:501-6.

  5. Guido M, Rugge M. Liver biopsy sampling in chronic viral hepatitis. Sem Liv Dis. 2004, in press.

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  Conflict of Interest:
  None declared.

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